April 2019, ScientificAmerican.com 43lier than it normally would have been. Garin responded with her
own warning: medical practitioners who engaged in “misinfor-
mation” on Dengvaxia would be responsible for every death from
dengue that could have been prevented by the vaccine.
There the matter rested until November 2017, when Sanofi Pas-
teur issued its own advisory: those who had never experienced a
dengue infection should not get Dengvaxia. A month later the
WHO issued fresh guidelines, recommending the vaccine only for
those with a “documented past dengue infection.” The Philippines
halted the vaccination program that December even as parents
and the press responded with fury, recriminations and further re-
ports of children’s deaths. More than 830,000 schoolchildren had
been vaccinated. According to the Department of Health (DOH),
as of September 2018, 154 of the vaccinated children had died of
various illnesses. The vast majority of these fatalities were unrelat-
ed to the vaccine, but clinical observations or blood tests con-
firmed that 19 of them had been caused by dengue.
Sanofi Pasteur contends that the deaths in the Philippines
could have arisen from a failure of the vaccine to protect a small
fraction of those vaccinated. In contrast, some experts argue, as
Dans and Dans did, that Dengvaxia mimics a prior encounter
with dengue—which can prime a patient’s body to respond in a
dangerous way to a second dengue infection.
The controversy has not slowed down the rollout of Dengvax-
ia, which is currently licensed in more than 20 countries. In Oc-
tober 2018 the U.S. Food and Drug Administration announced
that it would prioritize review of Sanofi Pasteur’s application to
approve Dengvaxia. That means it could be approved in the U.S.,
for use in dengue-endemic areas such as Puerto Rico, before the
Philippines completes its investigation into the deaths of vacci-
nated children—and before Sanofi Pasteur publishes its final re-
port from the six-year-long clinical trials.
A BAFFLING DISEASE
For most viruses, such as measles, the second bout, if it occurs
at all, is much milder than the first. For dengue, a second bout
is far more likely to kill. Scientists and doctors have struggled
for years to understand why this is so. In the 1950s and 1960s,
when epidemics of severe dengue began to rise in Asia, they
wondered if they were dealing with an altogether new infection.
The dengue they were familiar with kept patients bedridden
and fatigued, but this new manifestation sent them to the hos-
pital or the morgue. Had the virus mutated? Or was the im-
mune system to blame?
A young scientist fresh out of medical school was seeking an
answer. Scott B. Halstead began to study mosquito-borne viruses
in 1957, while working for the U.S. Army in Japan. He confronted
his first major dengue outbreak four years later, when stationed
at a military laboratory next door to the Bangkok Children’s Hos-
pital. Doctors thought the youngsters who were carried into the
hospital had been poisoned; almost a quarter of them died. Hal-
stead led the team that identified dengue as the cause of the out-
break. He went on to make a second, more baffling, discovery.
Children who were infected with dengue for a second time—each
time with a different dengue virus—and babies born to mothers
who were immune to dengue were most at risk for severe dengue
and death. No one could explain why.
In 1964 R. A. Hawkes, then a researcher at Australian Na-
tional University in Canberra, found that cell cultures infected
with Murray Valley encephalitis, West Nile, Japanese encephali-
tis or Getah viruses infected more cells when the virus was
mixed with antibodies compared with the virus alone. Hawkes
proposed that the antibodies were stabilizing the virus and in-
creasing their ability to attach to cells. Independently, Halstead
was wondering if much the same was happening with dengue.
To understand why two different dengue infections were
needed to make the second one lethal, Halstead infected 118
monkeys with different combinations of the four dengue virus-
es and measured the amount of virus in their blood. In 1973 he
published his results: some monkeys, which were infected a
second time and with a different dengue virus, had much high-
er viral loads. Four years later he provided a possible explana-
tion, calling it antibody-dependent enhancement.
Say your first infection is with the dengue virus called
DENV-1. Antibodies against that virus can linger in your blood
for decades, even your entire life. When you are infected a sec-
ond time with a different dengue virus, say DENV-2, 3 or 4, the
antibodies against DENV-1 could paradoxically accelerate the
replication of the new virus inside infected cells, precipitating a
potentially fatal dengue infection.
Since refined by Halstead and other researchers, the ADE
mechanism goes as follows: A dengue virus is a string of ribonu-
cleic acid enclosed in a protein capsule, which features an array of
characteristic protuberances on its surface. During a first infec-
tion with dengue, the immune system’s B cells make an antibody
called immunoglobulin G, or IgG, which latches onto one or more
of these irregularities. On attachment, the antibodies can deliver
the virus to immune system cells such as macrophages. The word
“phage” derives from the Greek word meaning “to eat”: macro-
phages are literally “big eaters.” They engulf the virus and digest it
with enzymes. Thus, once it is bound to antibodies, the dengue vi-
rus is normally trapped and destroyed inside macrophages.
When an infection is over, some antibody-making B cells be-
come dormant. In the event of a second infection with a different
dengue virus, these cells wake up to churn out the exact same an-
tibodies as before. Halstead postulated that some of these anti-
bodies can still stick to the surface of the unfamiliar virus but of-
ten fail to block its most lethal protrusions—its guns, so to speak.
The antibodies still deliver the intruder to macrophages but with-
out having disarmed it. That enables the virus to immobilize the
macrophage’s own defense system and take over the cell, whose
resources it then uses to churn out more copies of itself. The anti-
body’s unwitting assistance helps the new dengue variety pro-
duce 1,000 times more copies of itself than if it were acting alone.
Halstead’s reward for coming up with the ADE hypothesis
was a mix of indifference or disbelief from his peers, he recalls.
Today, at 89 years old, he is an adjunct professor at the Uni-
formed Services University of the Health Sciences in Bethesda,
Md., where he continues to argue his case. Many dengue ex-
perts describe him as the Godfather of ADE. “Back then, I was
thinking I’ve made a discovery that’s very important,” he says.
“Except nobody wanted to believe ADE was real.”
More than four decades later Eva Harris, a dengue expert at
the University of California, Berkeley, found strong evidence
that ADE was not only real but that it contributed to severe den-
gue disease in children. Harris had not set out to prove or dis-
prove ADE: she was initially skeptical of the phenomenon and
not all that keen on engaging in the decades-long debate. Instead